Background    Why do patients get nauseated and/or vomit after receiving an opioid?  Commonly described as an “allergy”, opioid-induced nausea (OIN) is not an allergic reaction.  In fact, rather than indicating a pathologic reaction, OIN indicates normal functioning of the brain. It occurs through the following mechanisms: 

• At the base of the 4th ventricle lies the chemoreceptor trigger zone (CTZ), a “sampling port”, to detect substances that do not belong in the blood.  Adjacent to the CTZ lies the medullary vomiting center (VC) which controls the complex muscular sequence of vomiting.  When the CTZ detects a noxious chemical in the blood, a neurochemical signal is sent to the VC and the vomiting reflex is initiated. Of note, this is the same mechanism when patients vomit after receiving chemotherapy.  
• Opioids can directly stimulate the vestibular apparatus—patients note a spinning sensation with their nausea. 
• Opioids cause constipation which can lead to nausea via stimulation of afferent cholinergic pathways. 

Do all opioids produce the same degree of OIN?  There is little research data on this topic.  In clinical practice, morphine and codeine are often mentioned as the worst offenders. Some clinical studies along with preclinical data in rats suggest that the transdermal fentanyl patch may have less nausea and constipation than morphine. 

Why are some patients more sensitive to the emetic effects of opioids than others?  Unknown 

What is the natural history of OIN?  Most patients develop tolerance to the emetic effects, so that within 3-7 days, at a constant opioid dose, the emetic effect will abate. On this basis, some experts advocate for co-prescription of antiemetics for the first 1-2 weeks of opioid use in opioid-naïve patients. 

What are management approaches? 

• Dose adjustment. If good pain relief is achieved but associated with OIN, it may be possible to lower the opioid dose, still retain good analgesia, and eliminate the nausea. 
• “Start low, go slow” opioid initiation.  Evidence suggests that starting opioids at a low dose and increasing the dose if needed in small increments can minimize the side effects like OIN. This is particularly relevant when target doses are low enough (e.g., morphine dosed at 1 mg orally twice daily for COPD-related dyspnea) and symptoms are mild enough that a rapid opioid escalation is not necessary. 
• Switch opioids (aka opioid rotation).  There is individual variability in emetic reaction to different opioids. Hence, just because a patient experiences nausea with one opioid (e.g., morphine), they may not experience nausea with another opioid (e.g., hydromorphone).  Of note though: since tolerance to OIN develops over 1-2 weeks, it can be difficult to know if a reduction in nausea is from the opioid rotation or tolerance. 
• Add an anti-emetic. Whenever possible, choose a drug directed at the most likely cause of nausea (see Fast Fact #5).  There are little published data to guide physicians in specific choice of anti-emetic for opioid-induced nausea. 
  • Consider starting with a low-cost anti-emetic with published evidence supporting its effectiveness for OIN.   Metoclopramide may have the most established evidence as cost-effective OIN treatment. Ondansetron over time has become more affordable so is a reasonable alternative, however, ondansetron can worsen opioid induced constipation. 
  • Antihistamines (e.g., loratadine, cetirizine) may help patients who note a spinning sensation.   
• Non-pharmacological approaches: while there is little evidence to support non-pharmacological treatments specifically for OIN, acupuncture, acupressure, behavioral treatments, and inhaled isopropyl alcohol are low-risk options that may provide some benefit based on their supporting evidence for other types of nausea. 

References 

1. Hardman JG, Limbird LE, et al, eds. Goodman and Gillman’s The Pharmacological Basis of Therapeutics. 9th Ed. New York, NY: McGraw-Hill; 1996. 
2. Herndon CM, et al. Management of opioid-induced gastrointestinal effects in patients receiving palliative care.  Pharmacotherapy. 2002; 22:240-250. 
3. Glare P, et al.  Systemic review of the efficacy of antiemetics in the treatment of nausea in patients with far-advanced cancer. Support Care Cancer. 2004; 12:432-440. 
4. Hardy J, et al. A double-blind, randomised, parallel group, multinational, multicentre study comparing a single dose of ondansetron 24 mg p.o. with placebo and metoclopramide 10 mg t.d.s. p.o. in the treatment of opioid-induced nausea and emesis in cancer patients. Support Care Cancer. 2002; 10:231-236. 
5. Pan CX, et al. Complementary and aternative medicine in the management of pain, dyspnea nd nausea and vomiting near the end-of-life: a systematic review. J Pain Sym Manage. 2000; 20:374-387. 
6. Megens AHP, Artois K, et al.  Comparison of the analgesic and intestinal effects of fentanyl and morphine in rats.  Journal of Pain and Symptom Management 1998; 15: 253-7. 
7. Ahmedzai S, Allan E, et al. The TTS-fentanyl multicenter study group: transdermal fentanyl in cancer pain J Drug Dev 1994;6: 93-7. 
8. Bruera E, Higginson IJ, Gunten CFV, Morita T. Textbook of Palliative Medicine and Supportive Care. CRC Press; 2021. 
9. Rocker GM, Simpson AC, Joanne YBHS et al. Opioid therapy for refractory dyspnea in patients with advanced chronic obstructive pulmonary disease: patients’ experiences and outcomes. CMAJ Open. 2013; 1: E27-36. 

Version History:  This Fast Fact was originally edited by David E Weissman MD.  2nd Edition published July 2005; 3rd Edition May 2015; 4th edition edited by Francois-Blumenfeld-Kouchner DO in March 2024.
Conflicts of Interest: None to report.